Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia

Abstract

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2-T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions

“…Polycythemia vera (PV), a myeloproliferative neoplasm (MPN), is characterized by the presence of a mutated, activated form of the tyrosine kinase JAK2. 1 In 95% of cases, PV patients present the V617F mutation in exon 14 (JAK2-V617F) and half of V617F-negative PV patients carry mutations or deletions in exon 12. 2 Both types of mutations result in activation of JAK2 and STAT5.…”

“…However, knock-in mouse models have demonstrated that CBFB-MYH11 alone is not sufficient to cause a leukemic phenotype and that additional aberrations were essential for the development of AML. 1 Secondary cytogenetic abnormalities occur in B40% of cases with þ 22, þ 8 (10-15% each), and del(7q) or þ 21 is most commonly observed. Recent molecular analyses have also provided important insights into the pathogenesis of myeloid disorders, and the commonly detected mutations of KIT and NRAS genes as well as deregulated CEBPA expression have been identified as likely candidates for cooperating events in CBF-positive AML.…”

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

“…Interestingly, a retroviral genetic screen, involving neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A followed by analysis of the insertion sites, has identified Plag1 and Plagl2 among the genes which independently cooperate with CBFB-MYH11 fusion gene in leukemogenesis (Castilla et al, 2004). AML subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11, encoding CBFbeta-SMMHC fusion protein.…”

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

“…Runt-related transcription factor-2 regulation and transcriptional activity are linked with increased growth, invasion, and metastasis in breast cancer (Barnes et al, 2003), prostate cancer (Brubaker et al, 2003;Pratap et al, 2005), colorectal cancer (Wai et al, 2006), lymphoma, leukaemia and myeloma (Wotton et al, 2002;Castilla et al, 2004;Colla et al, 2005;Blyth et al, 2006).…”